Process for the preparation of piperazinyl and diazepanyl benzamide derivatives

ABSTRACT

The present invention is directed to a novel process for the preparation of piperazinyl and diazepanyl benzamide derivatives, useful for the treatment of disorders and conditions mediated by a histamine receptor, preferably the H3 receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/870,003, filed Dec. 14, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is directed to a novel process for the preparationof piperazinyl and diazepanyl benzamide derivatives, useful for thetreatment of disorders and conditions mediated by a histamine receptor,preferably the H3 receptor.

BACKGROUND OF THE INVENTION

US Patent Application Publication 2004-0110746 A1, published Apr. 21,2005 (also published as PCT Publication WO 04/037801, May 6, 2004),which is hereby incorporated by reference, discloses novel piperazinyland diazepanyl benzamide derivatives useful for the treatment ofhistamine receptor mediated disorders. More specifically, the compoundsare useful for the treatment of disorders and conditions mediated by theH₃ receptor. More particularly, the compounds are useful for treating orpreventing neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis in a subject in need thereof. For example, methodsfor preventing, inhibiting the progression of, or treating upper airwayallergic response, asthma, itch, nasal congestion and allergic rhinitis.

US Patent Application Publication 2004-0110746 A1, published Apr. 21,2005 (also published as PCT Publication WO 04/037801, May 6, 2004)discloses a process for the preparation of the piperazinyl anddiazepanyl benzamides. There remains a need for processes for thepreparation of piperazinyl and diazepanyl benzamide derivatives that aresuitable for large scale/commercial applications.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation of acompound of formula (I)

or a pharmaceutically acceptable salt, ester, tautomer, solvate or amidethereof;

wherein

R¹ is selected from the group consisting of C₁₋₁₀alkyl (preferably,C₁₋₄alkyl), C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl;

n is an integer from 1 to 2 (preferably, n is 1);

R² and R³ are each independently selected from the group consisting ofhydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl andC₁₋₃alkoxy (preferably, R² and R³ are each hydrogen);

m is an integer from 1 to 7; (preferably, m is an integer from 1 to 4,more preferably, m is 1);

Q is NR⁸R⁹;

wherein R⁸ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene;

and R⁹ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl,6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene;

alternatively, Q is a saturated 3-12 membered N-linked heterocyclyl,wherein, in addition to the N-linking nitrogen, the 3-12 memberedheterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and N;

wherein Q (when Q is a saturated 3-12 membered N-linked heterocyclyl) isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydroxy, halo, carboxamide, C₁₋₆alkyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃alkylene, C₁₋₆alkoxy, (C₃₋₆cycloalkyl)-O—,phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—;

where each of the above heterocyclyl, phenyl, and alkyl groups may befurther optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of trifluoromethyl,methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;

provided that the 5- and 6-positions on the phenyl ring areunsubstituted (i.e., the R², R³ and —(CH₂)_(m)-Q are bound to the 2-, 3-and 4-positions on the phenyl ring);

provided further that when R¹ is methyl, then —(CH₂)_(m)-Q is notpiperidin-1-ylmethyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

reacting a compound of formula (X) with a compound of formula (XI); inthe presence of a peptide coupling agent; in an organic solvent ormixture thereof; to yield the corresponding compound of formula (I).

The present invention is further directed to a process for thepreparation of a compound of formula (I)

or a pharmaceutically acceptable salt, ester, tautomer, solvate or amidethereof;

wherein

R¹ is selected from the group consisting of C₁₋₁₀alkyl (preferably,C₁₋₄alkyl), C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl;

n is an integer from 1 to 2 (preferably, n is 1);

R² and R³ are each independently selected from the group consisting ofhydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, methyl andC₁₋₃alkoxy (preferably, R² and R³ are each hydrogen);

m is an integer from 1 to 7; (preferably, m is an integer from 1 to 4,more preferably, m is 1);

Q is NR⁸R⁹;

wherein R⁸ is selected from the group consisting of hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, 3-9 membered carbocyclyl, 3-12 membered heterocyclyl(preferably 5-9 or 5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene and (phenyl)C₁₋₆alkylene;

and R⁹ is selected from the group consisting of C₁₋₆alkyl, C₃₋₆alkenyl,6-9 membered carbocyclyl, 3-12 membered heterocyclyl (preferably 5-9 or5-8-membered heterocyclyl), phenyl, (6-9-memberedheterocyclyl)C₁₋₆alkylene, and (phenyl)C₁₋₆ alkylene;

alternatively, Q is a saturated 3-12 membered N-linked heterocyclyl,wherein, in addition to the N-linking nitrogen, the 3-12 memberedheterocyclyl may optionally contain between 1 and 3 additionalheteroatoms independently selected from O, S, and N;

wherein Q (when Q is a saturated 3-12 membered N-linked heterocyclyl) isoptionally substituted with 1-3 substituents independently selected fromthe group consisting of hydroxy, halo, carboxamide, C₁₋₆alkyl, 5-9membered or 6-9 membered heterocyclyl, —N(C₁₋₆ alkyl)(5-9 membered or6-9 membered heterocyclyl), —NH(5-9 membered or 6-9 memberedheterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9 membered or6-9 membered heterocyclyl)C₁₋₃alkylene, C₁₋₆alkoxy, (C₃₋₆cycloalkyl)-O—,phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—;

where each of the above heterocyclyl, phenyl, and alkyl groups may befurther optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of trifluoromethyl,methoxy, halo, nitro, cyano, hydroxy and C₁₋₃alkyl;

provided that the 5- and 6-positions on the phenyl ring areunsubstituted (i.e., the R², R³ and —(CH₂)_(m)-Q are bound to the 2-, 3-and 4-positions on the phenyl ring);

provided further that when R¹ is methyl, then —(CH₂)_(m)-Q is notpiperidin-1-ylmethyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

activating a compound of formula (X), to yield the correspondingcompound of formula (XII), wherein L is a leaving group;

reacting the compound of formula (XII) with a compound of formula (XI);in the presence of a tertiary organic or inorganic base; in a solvent ormixture of solvents; to yield the corresponding compound of formula (I).

In an embodiment, the present invention is directed to processes for thepreparation of a compound of formula (Ia)

also known as(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,or its pharmaceutically acceptable salt thereof, preferably thecorresponding di-hydrochloride salt.

In another embodiment, the present invention is directed to processesfor the preparation of a compound of formula (Ib)

also known as(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,or its pharmaceutically acceptable salt thereof, preferably thecorresponding mono-succinate salt.

The present invention is further directed to a process for thepreparation of the compound of formula (XI)

wherein R¹ is selected from the group consisting of C₁₋₁₀alkyl(preferably, C₁₋₄alkyl), C₃₋₈ alkenyl, C₃₋₈cycloalkyl, (C₃₋₈cycloalkyl)C₁₋₆ alkyl, (C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈alkylcarbonyl)C₁₋₈alkyl;

and wherein each of the above alkyl, alkylene, alkenyl, heterocyclyl,cycloalkyl, carbocyclyl, and aryl groups may each be independently andoptionally substituted with between 1 and 3 substituents independentlyselected from the group consisting of trifluoromethyl, methoxy, halo,amino, nitro, hydroxy and C₁₋₃ alkyl;

comprising

reacting a compound of formula (XX), wherein X is hydrogen or a nitrogenprotecting group and Z is a leaving group, with a compound of formula(XXI); in an organic solvent; to yield the corresponding compound offormula (XI).

In an embodiment, the present invention is further directed to a processfor the preparation of the compound of formula (XIa)

also known as 1-cyclopropyl-piperazine. The compound of formula (XIa) isuseful as a intermediate in the synthesis of compounds of formula (I)and more particularly, in the synthesis of the compound of formula (Ia).

In another embodiment, the present invention is further directed to aprocess for the preparation of the compound of formula (XIb)

also known as 1-isopropyl-piperazine. The compound of formula (XIb) isuseful as a intermediate in the synthesis of compounds of formula (I)and more particularly, in the synthesis of the compound of formula (Ib).

The present invention is further directed to a product preparedaccording to any of the processed described herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a product prepared accordingto any of the processes described herein. An illustration of theinvention is a pharmaceutical composition made by mixing a productprepared according to any of the processes described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing aproduct prepared according to any of the processes described herein anda pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedby histamine, preferably, the H₃ histamine receptor, (selected from thegroup consisting of neurologic disorders including sleep/wake andarousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy, eating disorders, obesity, motion sickness, vertigo,schizophrenia, substance abuse, bipolar disorders, manic disorders anddepression, as well as other histamine H₃ receptor mediated disorderssuch as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis) comprising administering to a subject in needthereof, a therapeutically effective amount of a products preparedaccording to any of the processes described herein or a pharmaceuticalcomposition as described above.

Another example of the invention is the use of a product preparedaccording to any of the processes described herein in the preparation ofa medicament for treating: (a) a sleep/wake disorder, (b) anarousal/vigilance disorders, (c) insomnia, (d) jet lag, (e) attentiondeficit hyperactivity disorders (ADHD), (f) a learning disorder, (g) amemory disorder, (h) cognitive dysfunction, (i) migraine, (j) neurogenicinflammation, (k) dementia, (l) mild cognitive impairment(pre-dementia), (m) Alzheimer's disease, (n) epilepsy, (O) narcolepsy,(p) an eating disorder, (q) obesity, (r) motion sickness, (s) vertigo,(t) schizophrenia, (u) substance abuse, (v) bipolar disorder, (w) manicdisorder, (x) depression, (y) upper airway allergic response, (z)asthma, (aa) itch, (bb) nasal congestion or (cc) allergic rhinitis, in asubject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to processes for the preparation ofcompounds of formula (I)

and pharmaceutically acceptable salts, esters, tautomers, solvates oramides thereof; wherein R¹, R², R³, n, m and Q are as herein defined.The compounds formula (I) of the present invention are useful for thetreatment of disorders and conditions mediated by a histamine receptor,preferably the H3 receptor.

Particularly, the compounds may be used in methods for treating orpreventing neurologic or neuropsychiatric disorders including sleep/wakeand arousal/vigilance disorders (e.g. insomnia and jet lag), attentiondeficit hyperactivity disorders (ADHD), learning and memory disorders,cognitive dysfunction, migraine, neurogenic inflammation, dementia, mildcognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,narcolepsy with or without associated cataplexy, cataplexy, disorders ofsleep/wake homeostasis, idiopathic somnolence, excessive daytimesleepiness (EDS), circadian rhythm disorders, sleep/fatigue disorders,fatigue, drowsiness associated with sleep apnea, sleep impairment due toperimenopausal hormonal shifts, Parkinson's-related fatigue, MS-relatedfatigue, depression-related fatigue, chemotherapy-induced fatigue,eating disorders, obesity, motion sickness, vertigo, schizophrenia,substance abuse, bipolar disorders, manic disorders and depression, aswell as other disorders in which the histamine H₃ receptor is involved,such as upper airway allergic response, asthma, itch, nasal congestionand allergic rhinitis in a subject in need thereof. For example, theinvention features methods for preventing, inhibiting the progressionof, or treating upper airway allergic response, asthma, itch, nasalcongestion and allergic rhinitis. Excessive daytime sleepiness (EDS) mayoccur with or without associated sleep apnea, shift work, fibromyalgia,MS, and the like.

The compounds of the present invention may be used in methods fortreating or preventing disease states selected from the group consistingof: cognitive disorders, sleep disorders, psychiatric disorders, andother disorders.

Cognitive disorders include, for example, dementia, Alzheimer's disease(Panula, P. et al., Soc. Neurosci. Abstr. 1995, 21, 1977), cognitivedysfunction, mild cognitive impairment (pre-dementia), attention deficithyperactivity disorders (ADHD), attention-deficit disorders, andlearning and memory disorders (Barnes, J. C. et al., Soc. Neurosci.Abstr. 1993, 19, 1813). Learning and memory disorders include, forexample, learning impairment, memory impairment, age-related cognitivedecline, and memory loss. H₃ antagonists have been shown to improvememory in a variety of memory tests, including the elevated plus maze inmice (Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), atwo-trial place recognition task (Orsetti, M. et al. Behav. Brain Res.2001, 124(2), 235-242), the passive avoidance test in mice (Miyazaki, S.et al. Meth. Find. Exp. Clin. Pharmacol. 1995, 17(10), 653-658) and theradial maze in rats (Chen, Z. Acta Pharmacol. Sin. 2000, 21(10),905-910). Also, in the spontaneously hypertensive rat, an animal modelfor the learning impairments in attention-deficit disorders, H₃antagonists were shown to improve memory (Fox, G. B. et al. Behav. BrainRes. 2002, 131(1-2), 151-161).

Sleep disorders include, for example, insomnia, disturbed sleep,narcolepsy (with or without associated cataplexy), cataplexy, disordersof sleep/wake homeostasis, idiopathic somnolence, excessive daytimesleepiness (EDS), circadian rhythm disorders, fatigue, lethargy,REM-behavioral disorder, and jet lag. Fatigue and/or sleep impairmentmay be caused by or associated with various sources, such as, forexample, sleep apnea, perimenopausal hormonal shifts, Parkinson'sdisease, multiple sclerosis (MS), depression, chemotherapy, or shiftwork schedules.

Psychiatric disorders include, for example, schizophrenia (Schlicker, E.and Marr, I., Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 353,290-294), bipolar disorders, manic disorders, depression (Lamberti, C.et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336; Perez-Garcia, C. etal. Psychopharmacology 1999, 142(2), 215-220) (Also see: Stark, H. etal., Drugs Future 1996, 21(5), 507-520; and Leurs, R. et al., Prog. DrugRes. 1995, 45, 107-165 and references cited therein.),obsessive-compulsive disorder, and post-traumatic stress disorder.

Other disorders include, for example, motion sickness, vertigo(including vertigo and benign postural vertigo), tinitus, epilepsy(Yokoyama, H. et al., Eur. J. Pharmacol. 1993, 234, 129-133), migraine,neurogenic inflammation, eating disorders (Machidori, H. et al., BrainRes. 1992, 590, 180-186), obesity, substance abuse disorders, movementdisorders (e.g. restless leg syndrome), and eye-related disorders (e.g.macular degeneration and retinitis pigmentosis).

The present invention is further directed to processes for thepreparation of compounds of formula (XI)

wherein R¹ is as herein defined. The compounds of formula (XI) areuseful as intermediates in the preparation of the compounds of formula(I).

As used herein, “C_(a-b)” (where a and b are integers) refers to aradical containing from a to b carbon atoms inclusive. For example, C₁₋₃denotes a radical containing 1, 2 or 3 carbon atoms.

As used herein, “halo” or “halogen” shall mean monovalent radicals ofchlorine, bromine, fluorine and iodine.

As used herein, the term “alkyl”, whether used alone or as part of asubstituent group, shall include straight and branched saturated carbonchains. For example, alkyl radicals include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.Unless otherwise noted, “lower” when used with alkyl means a carbonchain composition of 1-4 carbon atoms. “Alkylene” refers to a bivalenthydrocarbyl group, such as methylene (—CH₂—), ethylene (—CH₂—CH₂—) orpropylene (—CH₂CH₂CH₂—), and so on.

As used herein, the term “alkylene” refers to a divalent straight- orbranched-chain alkyl group. Suitable examples include, but are notlimited to methylene, ethylene, n-propylene, and the like.

As used herein, unless otherwise noted, “alkenyl” shall mean an alkylenegroup with at least two hydrogen atoms replaced with a pi bond to form acarbon-carbon double bond, such as propenyl, butenyl, pentenyl, and soon. Where the alkenyl group is R⁸ or R⁹, the open radical (point ofattachment to the rest of the molecule) is on sp³ carbon, as illustratedby allyl, and the double bond or bonds is therefore at least alpha (ifnot beta, gamma, etc.) to the open radical.

As used herein, “alkylidene” refers to a saturated or unsaturated,branched, straight-chain or cyclic divalent hydrocarbon radical derivedby removal of two hydrogen atoms from the same carbon atom of a parentalkane, alkene or alkyne. The divalent radical center forms a doublebond with a single atom on the rest of the molecule. Typical alkylideneradicals include, but are not limited to, ethanylidene; propylidenessuch as propan-1-ylidene, propan-2-ylidene, cyclopropan-1-ylidene;butylidenes such as butan-1-ylidene, butan-2-ylidene,2-methyl-propan-1-ylidene, cyclobutan-1-ylidene; and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above-described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “cycloalkyl” shall denote athree- to eight-membered, saturated monocyclic carbocyclic ringstructure. Suitable examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, unless otherwise noted, “cycloalkenyl” shall denote athree- to eight-membered, partially unsaturated, monocyclic, carbocyclicring structure, wherein the ring structure contains at least one doublebond. Suitable examples include cyclohexenyl, cyclopentenyl,cycloheptenyl, cyclooctenyl, cyclohex-1,3-dienyl and the like.

As used herein, unless otherwise noted, “aryl” shall refer tocarbocyclic aromatic groups such as phenyl, naphthyl, and the like.Divalent radicals include phenylene (—C₆H₄—) which is preferablyphen-1,4-diyl, but may also be phen-1,3-diyl.

As used herein, unless otherwise noted, “aralkyl” shall mean any alkylgroup substituted with an aryl group such as phenyl, naphthyl, and thelike. Examples of aralkyls include benzyl, phenethyl, and phenylpropyl.

As used herein, unless otherwise noted, “carbocyclyl” shall mean anycyclic group consisting of 3-12 carbon atoms, and preferably 6-9 carbonatoms, in the skeleton ring or rings, if the carbocycle is a fused orspiro bicyclic or tricyclic group. A carbocycle may be saturated,unsaturated, partially unsaturated, or aromatic. Examples includecycloalkyl, cycloalkenyl, cycloalkynyl; specific examples includephenyl, benzyl, indanyl, and biphenyl. A carbocycle may havesubstituents that are not carbon or hydrogen, such as hydroxy, halo,halomethyl, and so on as provided elsewhere herein.

As used herein, unless otherwise noted, the terms “heterocycle”,“heterocyclyl” and “heterocyclo” shall denote any three-, four-, five-,six-, seven-, or eight-membered monocyclic, nine- or ten-memberedbicyclic, or thirteen- or fourteen-membered tricyclic ring structurecontaining at least one heteroatom moiety selected from the groupconsisting of NH, O, SO, SO₂, (C═O), and S, and preferably NH, O, or S,optionally containing one to four additional heteroatoms in each ring.In some embodiments, the heterocyclyl contains between 1 and 3 orbetween 1 and 2 additional heteroatoms. Unless otherwise specified, aheterocyclyl may be saturated, partially unsaturated, aromatic orpartially aromatic. The heterocyclyl group may be attached at anyheteroatom or carbon atom that results in the creation of a stablestructure.

Exemplary monocyclic heterocyclic groups can include pyrrolidinyl,pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazaolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, hexahydroazepinyl,4-piperidinyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl,thiiranyl, triazinyl, triazolyl, tetrazolyl, azetidinyl and the like.

For example, where Q is a saturated 3-12 membered N-linked heterocyclyl,Q necessarily contains at least one nitrogen, and the carbon atoms aresp³ hybridized. Where Q is a fused bicyclic heterocyclyl, the carbonatoms of the ring linked to L is sp³ hybridized, provided the adjacentring (and the common carbon atoms) may be sp², such as an indanyl whereone of the carbon atoms has been replaced with nitrogen.

In general, exemplary bicyclic heterocyclyls include benzthiazolyl,benzoxazolyl, benzoxazinyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo{2,3-c}pyridinyl, furo{3,1-b}pyridinyl), orfuro{2,3-b}pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl (such as1,2,3,4-tetrahydroquinolinyl), tetrahydroisoquinolinyl(such as1,2,3,4-tetrahydroisoquiunolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl,benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone,dihydrobenzopyranyl, indolinyl, isoindolyl, tetrahydroindoazolyl (suchas 4,5,6,7-tetrahydroindazolyl), isochromanyl, isoindolinyl,naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl,quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl,thienothienyl,

and the like.

Exemplary tricyclic heterocyclic groups include acridinyl, phenoxazinyl,phenazinyl, phenothiazinyl, carbozolyl, perminidinyl, phenanthrolinyl,carbolinyl, naphthothienyl, thianthrenyl, and the like.

Preferred heterocyclyl groups include morpholinyl, thiomorpholinyl,piperidinyl, piperazinyl, pyrrolidinyl, pyrimidinyl, pyridyl, pyrrolyl,imidazolyl, oxazolyl, isoxazolyl, acridinyl, azepinyl,hexahydroazepinyl, azetidinyl, indolyl, isoindolyl, thiazolyl,thiadiazolyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl,1,3,4-trihydroisoquinolinyl, 4,5,6,7-tetrahydroindadolyl, benzoxazinyl,benzoaxzolyl, benzthiazolyl, benzimidazolyl, tetrazolyl, oxadiazolyl,

As used herein, unless otherwise noted, the term “heterocyclyl-alkyl” or“heterocyclyl-alkylene” shall denote any alkyl group substituted with aheterocyclyl group, wherein the heterocycly-alkyl group is bound throughthe alkyl portion to the central part of the molecule. Suitable examplesof heterocyclyl-alkyl groups include, but are not limited topiperidinylmethyl, pyrrolidinylmethyl, piperidinylethyl,piperazinylmethyl, pyrrolylbutyl, piperidinylisobutyl, pyridylmethyl,pyrimidylethyl, and the like.

When a particular group is “substituted” (e.g., alkyl, alkylene,cycloalkyl, aryl, heterocyclyl, heteroaryl), that group may have one ormore substituents, preferably from one to five substituents, morepreferably from one to three substituents, most preferably from one totwo substituents, independently selected from the list of substituents.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl(alkyl)amido(alkyl)” substituent refers to agroup of the formula

Unless otherwise noted, the position on the core phenyl ring of thecompounds of formula (I) to which the R², R³ and —(CH₂)_(m)-Qsubstituent groups are bound shall be defined as numbered in a clockwisedirection around the phenyl ring, beginning with the carbon atom towhich the —C(O)— group is bound, as drawn below

In the compounds of formula (I) of the present invention, R², R³ and—(CH₂)_(m)-Q may be bound at the 2-, 3- and/or 4-positions only.Further, the 5- and 6-positions are unsubstituted. Thus, in thecompounds of formula (I), the positions to which R², R³ and —(CH₂)_(m)-Qare bound may be as listed below:

2-position 3-position 4-position R² R³ —(CH₂)_(m)-Q R³ R² —(CH₂)_(m)-QR² —(CH₂)_(m)-Q R³ R³ —(CH₂)_(m)-Q R² —(CH₂)_(m)-Q R² R³ —(CH₂)_(m)-Q R³R²

Abbreviations used in the specification, particularly in the Schemes andExamples, are as follows

BOC=t-Butoxycarbonyl

Cbz=Benzyloxycarbonyl

CDI=1,1-carbonyldiimidazole

DCC═N,N′-Dicyclohexyl-carbodiimide

DIPEA=Diisopropyl ethyl amine

DMF=Dimethylformamide

ECF=Ethylchloroformate

EDAC=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N″,N″-TetramethyluroniumHexafluorophosphate

HBTU=O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HOBt=1-Hydroxybenzotriazole

HPLC=High Performance Liquid Chromatography

IBCF=Isobutylchloroformate

IPA=Isopropyl Alcohol

NaBH(OAc)₃=Sodium triacetoxyborohydride

NMR=Nuclear Magnetic Resonance

OBt=—O-(1-benzotriazolyl)

OMs=—O-mesyl (-O—SO₂—CH₃)

OTf=—O-triflyl (-O—SO₂—CF₃)

OTs=—O-tosyl (O—SO₂-(4-methylphenyl))

TBTU=O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtertafluoroborate

TEA or Et₃N=Triethylamine

THF=Tetrahydrofuran

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes prevention, inhibition of onset, oralleviation of the symptoms of the disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, imidazolyl, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumeric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein R¹ is selected from thegroup consisting of C₁₋₆alkyl (preferably isopropyl) and C₃₋₈cycloalkyl(preferably cyclopropyl or cyclobutyl); n is 1; R² and R³ are eachhydrogen; R⁴ is —(CH₂)-Q; and Q is a 5- to 6-membered N-linkedheterocyclyl, wherein in addition to N-linking nitrogen, theheterocyclyl may optionally contain between 1 and 2 additionalheteroatoms independently selected form O, S and NH.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) wherein:

(a) n is 1;

(b) R¹ is C₁₋₁₀ alkyl (preferably branched);

(c) R¹ is branched C₃₋₅ alkyl;

(d) one of R², R³ and R⁴ is G; (preferably one of R³ and R⁴ is G)

(e) R⁴ is G;

(f) L is unbranched —(CH₂)_(m)—, wherein m is an integer from 1 to 4;

(g) L is —CH₂—;

(h) Q is a saturated N-linked nitrogen-containing heterocyclyl;

(i) Q is substituted or unsubstituted piperidinyl, diazepanyl, azepanyl,decahydroisoquinolin-2-yl, piperazinyl, pyrrolinyl, pyrrolidinyl,thiomorpholinyl, or morpholinyl;

(j) Q is unsubstituted diazepanyl, azepanyl, morpholinyl,decahydroisoquinolin-2-yl, piperidinyl, or pyrrolidinyl;

(k) substituted Q are selected from N—(C₁₋₆ alkyl)piperazinyl,N-phenyl-piperazinyl, 1,3,8-triaza-spiro{4.5}decyl, and1,4-dioxa-8-aza-spiro{4.5}decyl;

(l) Q is a monovalent radical of an amine selected from aziridine,1,4,7-trioxa-10-aza-cyclododecane, thiazolidine,1-phenyl-1,3,8-triaza-spiro{4.5}decan-4-one, piperidine-3-carboxylicacid diethylamide, 1,2,3,4,5,6-hexahydro-{2,3′}bipyridinyl,4-(3-trifluoromethyl-phenyl)-piperazine, 2-piperazin-1-yl-pyrimidine,piperidine-4-carboxylic acid amide, methyl-(2-pyridin-2-yl-ethyl)-amine,{2-(3,4-dimethoxy-phenyl)-ethyl}-methyl-amine, thiomorpholinyl,allyl-cyclopentyl-amine, {2-(1H-indol-3-yl)-ethyl}-methyl-amine,1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one,2-(piperidin-4-yloxy)-pyrimidine, piperidin-4-yl-pyridin-2-yl-amine,phenylamine, and pyridin-2-ylamine;

(m) Q is selected from diazepanyl, azepanyl, morpholinyl, piperidinyl,and pyrrolidinyl, optionally substituted with between 1 and 3substituents independently selected from hydroxy, halo, carboxamide,C₁₋₆ alkyl, 5-9 membered or 6-9 membered heterocyclyl, —N(C_(i-6)alkyl)(5-9 membered or 6-9 membered heterocyclyl), —NH(5-9 membered or6-9 membered heterocyclyl), —O(5-9 or 6-9 membered heterocyclyl), (5-9membered or 6-9 membered heterocyclyl)C₁₋₃ alkylene, C₁₋₆ alkoxy, (C₃₋₆cycloalkyl)-O—, phenyl, (phenyl)C₁₋₃ alkylene, and (phenyl)C₁₋₃alkylene-O—, where each of above heterocyclyl, phenyl, and alkyl groupsmay be optionally substituted with from 1 to 3 substituentsindependently selected from trifluoromethyl, methoxy, halo, nitro,cyano, hydroxy, and C₁₋₃ alkyl;

(n) Q is substituted with a substituent comprising a 5-9 membered or 6-9membered heterocyclyl group selected from: pyridyl, pyrimidyl, furyl,thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene, oxazolyl, thiazolyl,2,3-dihydro-indolyl, benzimidazolyl, 2-oxobenzimidazolyl,(tetrazolyl)C₁₋₆ alkylene, tetrazolyl, (triazolyl)C₁₋₆ alkylene,triazolyl, (pyrrolyl)C₁₋₆ alkylene, pyrrolidinyl, and pyrrolyl;

(o) Q is piperidinyl;

(p) R⁸ is hydrogen;

(q) R⁹ is C₁₋₆ alkyl;

(r) R⁹ is unsubstituted or substituted phenyl;

(s) R⁸ and R⁹ independently are C₁₋₆ alkyl;

(t) R⁸ and R⁹ are methyl;

(u) R⁸ and R⁹ are ethyl;

(v) R⁹ is selected from phenyl or 5-9 membered aromatic heterocyclyl,wherein said phenyl or aromatic heterocyclyl is optionally substitutedwith 1-3 substituents selected from methoxy, hydroxy, halo, nitro,cyano, trifluoromethyl, and C₁₋₃ alkyl;

(w) R⁹ is selected from substituted or unsubstituted phenyl, pyridyl,pyrimidyl, furyl, thiofuryl, imidazolyl, (imidazolyl)C₁₋₆ alkylene,oxazolyl, thiazolyl, 2,3-dihydro-indolyl, benzimidazolyl,2-oxobenzimidazolyl, (tetrazolyl)C₁₋₆ alkylene, tetrazolyl,(triazolyl)C₁₋₆ alkylene, triazolyl, (pyrrolyl)C₁₋₆ alkylene,pyrrolidinyl, and pyrrolyl;

(x) R⁹ is substituted or unsubstituted pyridyl;

(y) X is O; and

(z) combinations of (a) through (z) above.

In another embodiment, the present invention is directed to processesfor the preparation of compounds of formula (I) selected from the groupconsisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;-   (4-Butyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(3-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(4-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {3-(4-Benzyl-piperidin-1-ylmethyl)-phenyl}-(4-methyl-piperazin-1-yl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(1-Ethyl-propyl)piperazin-1-yl}-{4-{(4-trifluoromethyl-phenylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   {4-(1-Methyl-heptyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   (4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

Preferably, the processes of the present invention are directed tomaking compounds selected from the group consisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(3-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(4-isopropyl-piperazin-1-ylmethyl)-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-{(5-trifluoromethyl-pyridin-2-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-{(6-trifluoromethyl-pyridin-3-ylamino)-methyl}-phenyl}-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Methyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-phenylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {-4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {-4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {-4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   {4-{(5-Chloro-pyridin-2-ylamino)-methyl}-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   (4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

Preferably, the present invention is directed to processes for thepreparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-{[Ethyl-(2-methoxy-ethyl)-amino]-methyl}-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Azepan-1-ylmethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Diethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Dimethylaminomethyl-phenyl)-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-{[(2-methoxy-ethyl)-propyl-amino]-methyl}-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-(4-thiomorpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-ethylamino)-methyl]-phenyl}-methanone;-   (4-Isopropyl-piperazin-1-yl)-[4-(pyridin-2-ylaminomethyl)-phenyl]-methanone;-   (4-Isopropyl-piperazin-1-yl)-{4-[(2-methoxy-1-methyl-ethylamino)-methyl]-phenyl}-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-{4-(decahydro-isoquinolin-2-ylmethyl)-phenyl}-methanone;-   {4-(Benzylamino-methyl)-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   {4-(Benzylamino-methyl)-phenyl}-{4-(1-ethyl-propyl)-piperazin-1-yl}-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   (4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

More preferably, the present invention is directed to processes for thepreparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-Azepan-1-ylmethyl-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone    dihydrochloride;-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Cyclohexyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Isopropyl-piperazin-1-yl)-{4-(3-trifluoromethyl-piperidin-1-ylmethyl)-phenyl}-methanone    dihydrochloride;-   (4-sec-Butyl-piperazin-1-yl)-(4-dimethylaminomethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   (4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

More preferably still, the present invention is directed to processesfor the preparation of a compound of formula (I) selected from the groupconsisting of:

-   (4-Azepan-1-ylmethyl-phenyl)-(4-sec-butyl-piperazin-1-yl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   (4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-piperidin-1-ylmethyl-phenyl)-methanone;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-pyrrolidin-1-ylmethyl-phenyl)-methanone;-   (4-sec-Butyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   {4-(1-Ethyl-propyl)-piperazin-1-yl}-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone;-   (4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone    dihydrochloride; and-   (4-Cyclobutyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone.

In an embodiment, the present invention is directed to processes for thepreparation of compounds of formula (I) or pharmaceutically acceptablesalts thereof, wherein R¹ is cycloalkyl, preferably cycylopropyl. Inanother embodiment, the present invention is directed to processes forthe preparation of compounds of formula (I) or pharmaceuticallyacceptable salts thereof, wherein R¹ is a branched alkyl, preferablyisopropyl.

In an embodiment of the present invention, the present invention isdirected to processes for the preparation of a compound selected fromthe group consisting of the compound of formula (Ia), the compound offormula (Ib) and pharmaceutically acceptable salts thereof. In anotherembodiment, the present invention is directed to processes for thepreparation of the compound selected from the group consisting of thecompound of formula (Ia), the dihydrochloride salt of the compound offormula (Ia), the compound of formula (Ib) and the mono-succinate saltof the compound of formula (Ib).

The present invention is directed to a process for the preparation ofcompounds of (I) as outlined in Scheme 1, below.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), a known compound orcompound prepared by known methods; wherein the compound of formula (XI)is preferably present in an amount in the range of from about 0.95 toabout 1.25 molar equivalents, or any range therein, more preferablyabout 1.1 molar equivalents;

in the presence of a suitably selected peptide coupling agent such asHOBt/EDAC, ECF, IBCF, CDI, HATU, HBTU, TBTU, DCC, and the like,preferably HOBt/EDAC; wherein the coupling agent is present in a amountin the range of from about a catalytic amount to about a 1 molarequivalent (relative to the molar amount of the compound of formula(X)), or any range therein, preferably, about 1 molar equivalent;

in an organic solvent or mixture thereof, such as toluene, acetonitrile,ethyl acetate, DMF, THF, methylene chloride, and the like, preferably amixture of toluene and acetonitrile at a ratio of about 4:1volume:volume;

to yield the corresponding compound of formula (I).

Alternatively, the compound of formula (X) is activated according toknown methods, to yield the corresponding compound of formula (XII),wherein L is a suitable leaving group such as chloro, bromo,—OC(O)—O—C₁₋₄alkyl, imidazolide, and the like, preferably chloro. Forexample, wherein the leaving group is chloro, the compound of formula(X) is activated by reacting with a suitably selected source of chlorinesuch as thionyl chloride, oxalyl chloride, and the like.

The compound of formula (XII) is reacted with a suitably substitutedcompound of formula (XI), a known compound or compound prepared by knownmethods; wherein the compound of formula (XI) is preferably present inan amount in the range of from about 1 to about 3 molar equivalents, orany range therein, preferably from about 1 to about 1.2 molarequivalents; in the presence of a suitably selected tertiary organic orinorganic base such as TEA, NaOH, Na₂CO₃, and the like, preferably aninorganic base, more preferably a 1:1 molar ratio mixture of NaOH andNa₂CO₃; wherein the tertiary organic or inorganic base is preferablypresent in an amount in the range of from about 4 to about 10 molarequivalents, or any range therein, more preferably, in an amount in therange of from about 4 to about 6 molar equivalents; in a solvent ormixture thereof, such as toluene, dichloromethane, THF, water, and thelike, preferably a mixture of toluene and water, wherein the molar ratioof toluene to water is preferably in the range of from about 2:1 toabout 1:2; to yield the corresponding compound of formula (I).

The compound of formula (I) may be optionally isolated according toknown methods, for example by filtration, solvent evaporation,distillation, and the like. The compound of formula (I) may be furtheroptionally purified according to known methods, for example byrecrystallization, column chromatography, and the like.

Alternatively, the compound of formula (I) may be reacted with asuitably selected acid, to yield the corresponding acid addition salt,which salt may be isolated and/or purified according to known methods.

In an embodiment, the present invention is directed to a process for thepreparation of the compound of formula (Ia), as described in more detailin Scheme 2 below.

Accordingly, a suitably substituted compound of formula (Xa), also knownas 4-morpholin-4-ylmethyl-benzoic acid, a known compound, is reactedwith a suitably substituted compound of formula (XIa), also known as1-cyclopropyl-piperazine, a known compound; wherein the compound offormula (XIa) is preferably present in an amount in the range of fromabout 0.95 to about 1.25 molar equivalents, more preferably about 1.1molar equivalents;

in the presence of a suitably selected peptide coupling agent such asHOBt/EDAC, ECF, IBCF, CDI, HATU, HBTU, TBTU, DCC, and the like.preferably HOBt/EDAC; wherein the coupling agent is present in a amountin the range of from about a catalytic amount to about a 1 molarequivalent (relative to the molar amount of the compound of formula(X)), preferably, about 1 molar equivalent;

in an organic solvent or mixture thereof, such as toluene, acetonitrile,ethyl acetate, DMF, THF, methylene chloride, and the like, preferably amixture of toluene and acetonitrile at a ratio of about 4:1volume:volume;

to yield the corresponding compound of formula (Ia).

Alternatively, the compound of formula (Xa) is activated according toknown methods, to yield the corresponding compound of formula (XIIa),wherein L is a suitable leaving group such as chloro, bromo,—OC(O)—O—C₁₋₄alkyl, imidazolide, and the like, preferably chloro. Forexample, wherein the leaving group is chloro, the compound of formula(Xa) is activated by reacting with a suitably selected source ofchlorine such as thionyl chloride, oxalyl chloride, and the like.

The compound of formula (XIIa) is reacted with a suitably substitutedcompound of formula (XIa), a known compound or compound prepared byknown methods; wherein the compound of formula (XIa) is preferablypresent in an amount in the range of from about 1 to about 3 molarequivalents, preferably from about 1 to about 1.2 molar equivalents; inthe presence of a suitably selected tertiary organic or inorganic basesuch as TEA, NaOH, Na₂CO₃, and the like, preferably an inorganic base,more preferably a 1:1 molar ratio mixture of NaOH and Na₂CO₃; whereinthe tertiary organic or inorganic base is preferably present in anamount in the range of from about 4 to about 10 molar equivalents, morepreferably, in an amount in the range of from about 4 to about 6 molarequivalents; in a solvent or mixture thereof, such as toluene,dichloromethane, THF, water, and the like, preferably a mixture oftoluene and water, wherein the molar ratio of toluene to water ispreferably in the range of from about 2:1 to about 1:2; to yield thecorresponding compound of formula (Ia).

The compound of formula (Ia) may be optionally isolated according toknown methods, for example by filtration, solvent evaporation,distillation, and the like. The compound of formula (Ia) may be furtheroptionally purified according to known methods, for example byrecrystallization, column chromatography, and the like. Preferably, thecompound of formula (Ia) is isolated by solvent evaporation and purifiedby salt formation as described below.

Alternatively, the compound of formula (Ia) is reacted with a suitablyselected acid, to yield the corresponding acid addition salt.Preferably, the compound of formula (Ia) is reacted with HCl acid, in anorganic solvent, preferably in an alcohol such as ethyl acetate, THF,dioxane, diethyl ethyl, IPA, ethanol, and the like, preferably, thecompound of formula (Ia) is reacted with ⅚N HCl in IPA, to yield thecorresponding acid addition salt. One skilled in the art will recognizethat for the compound of formula (Ia) reacted with ⅚N HCl, thecorresponding acid addition salt is a di-hydrochloride salt. Morespecifically, the process yields the crystalline, di-hydrochloride salt.

The crystalline di-hydrochloride salt of the compound of formula (Ia) isfurther optionally isolated and/or purified according to known methods,for example isolated by filtration, solvent evaporation, and the likeand purified by recrystallization, column chromatography, and the like.Preferably, the dihydrochloride salt of the compound of formula (Ia) ispurified by recrystallized from a mixture of ethanol and water, at aratio of 90 L:15 L.

In another embodiment, the present invention is directed to a processfor the preparation of the compound of formula (Ib), as described inmore detail in Scheme 3, below.

Accordingly, a suitably substituted compound of formula (Xb), also knownas also known as 4-morpholin-4-ylmethyl-benzoic acid, a known compound,is reacted with a suitably substituted compound of formula (XIb), alsoknown as 1-isopropyl-piperazine, a known compound; wherein the compoundof formula (XIa) is preferably present in an amount in the range of fromabout 0.95 to about 1.25 molar equivalents, more preferably about 1.1molar equivalents;

in the presence of a suitably selected peptide coupling agent such asHOBt/EDAC, ECF, IBCF, CDI, HATU, HBTU, TBTU, DCC, and the like.preferably HOBt/EDAC; wherein the coupling agent is present in a amountin the range of from about a catalytic amount to about a 1 molarequivalent (relative to the molar amount of the compound of formula(X)), preferably, about 1 molar equivalent;

in an organic solvent or mixture thereof, such as toluene, acetonitrile,ethyl acetate, DMF, THF, methylene chloride, and the like, preferably amixture of toluene and acetonitrile at a ratio of about 4:1volume:volume;

to yield the corresponding compound of formula (Ib).

Alternatively, the compound of formula (Xb) is activated according toknown methods, to yield the corresponding compound of formula (XII),wherein L is a suitable leaving group such as chloro, bromo,—OC(O)—O—C₁₋₄alkyl, imidazolide, and the like, preferably chloro. Forexample, wherein the leaving group is chloro, the compound of formula(Xb) is activated by reacting with a suitably selected source ofchlorine such as thionyl chloride, oxalyl chloride, and the like.

The compound of formula (XIIb) is reacted with a suitably substitutedcompound of formula (XIb), a known compound or compound prepared byknown methods; wherein the compound of formula (XIb) is preferablypresent in an amount in the range of from about 1 to about 3 molarequivalents, preferably from about 1 to about 1.2 molar equivalents; inthe presence of a suitably selected tertiary organic or inorganic basesuch as TEA, NaOH, Na₂CO₃, and the like, preferably an inorganic base,more preferably a 1:1 molar ratio mixture of NaOH and Na₂CO₃; whereinthe tertiary organic or inorganic base is preferably present in anamount in the range of from about 4 to about 10 molar equivalents, morepreferably, in an amount in the range of from about 4 to about 6 molarequivalents; in a solvent or mixture thereof, such as toluene,dichloromethane, THF, water, and the like, preferably a mixture oftoluene and water, wherein the molar ratio of toluene to water ispreferably in the range of from about 2:1 to about 1:2; to yield thecorresponding compound of formula (Ib).

The compound of formula (Ib) may be optionally isolated and/or purifiedaccording to known methods, for example by filtrations, solventevaporation, distillation, column chromatography, recrystallization, andthe like. Preferably, the compound of formula (Ib) is isolated bysolvent evaporation and purified by salt formation as described herein.

Alternatively, the compound of formula (Ib) is reacted with a suitablyselected acid, to yield the corresponding acid addition salt.Preferably, the compound of formula (Ib) is reacted with succinic acid,in an organic solvent such as THF, toluene, acetonitrile, and the like,preferably in an organic solvent in which succinic acid is soluble, morepreferably in THF, to yield the corresponding mono-succinate additionsalt.

The mono-succinate salt of the compound of formula (Ib) is furtheroptionally isolated and/or purified according to known methods.Preferably, the mono-succinate salt of the compound of formula (Ib) ispurified by recrystallization from a suitable solvent such as absoluteethanol, methanol, isopropyl alcohol, acetonitrile, and the like,preferably from absolute ethanol.

Compounds of formula (X) are known compounds or compounds which may beprepared according to known methods. As an example, Scheme 4 belowoutlines a process for the preparation of the compound of formula (Xa).

Accordingly, a suitably substituted compound of formula (XVa), alsoknown as 4-formyl-benzoic acid, a known compound or compound prepared byknown methods, is reacted with a suitably substituted compound offormula (XVIa), also known as morpholine, a known compound; wherein thecompound of formula (XVIa) is preferably present in an amount in therange of from about 1 to about 5 molar equivalents, or any rangetherein, more preferably, the compound of formula (XVIa) is present inan amount in the range of from about 1.5 to about 2.5 molar equivalents,more preferably still, the compound of formula (XVIa) is present in anamount in the range of from about 1.25 to about 1.5 molar equivalents;in the presence of a reducing agent such as NaBH(OAc)₃, NaBH₄, sodiumcyanoborohydride, and the like, preferably, NaBH(OAc)₃; wherein thereducing agent is preferably present in an amount in the range of fromabout 1 to about 2 equivalents, or any range therein, more preferably inan amount in the range of from about 1.25 to about 1.5 equivalents; inan organic solvent such as THF, toluene, acetonitrile, and the like,preferably, THF; to yield the corresponding compound of formula (Xa).Preferably, the compound of formula (Xa) is not isolated.

The compound of formula (Xa) is reacted with a suitably selected acid,such as HCl, as shown above, according to known methods, to yield thecorresponding acid addition salt of the compound of formula (Xa). Thecompound of formula (Xa) and/or the corresponding acid addition salt ofthe compound of formula (Xa) may be further, optionally isolated and/orpurified according to known methods such as filtration, solventevaporation, distillation, column chromatography, recrystallization, andthe like.

The present invention is further directed to a process for thepreparation of the compound of formula (XI), as outline in more detailin Scheme 5 below.

Accordingly, a suitably substituted compound of formula (XX), wherein Xis hydrogen or a suitably selected nitrogen protecting group such as—C(O)—CF₃, acetyl, benzoyl, BOC, Cbz, and the like, preferably, X ishydrogen or —C(O)—CF₃; and wherein Z is selected from suitable leavinggroups such as —OMs, —O—SO₂—OH, —OTf, —OTs, and the like, and whereinboth Z substituents are the same, preferably each Z is —OMs, a knowncompound or compound prepared according to known methods; is reactedwith a compound of formula (XXI), a known compound or compound preparedby known methods; wherein the compound of formula (XXI) is preferablypresent in an amount in the range of from about 1 to about 2 molarequivalents; or any range therein, in an organic solvent such as THF,toluene, DMF, 2-methyl-THF, acetonitrile, and the like, preferably THF;to yield the corresponding compound of formula (XI).

Alternatively, when X is hydrogen, the compound of formula (XX) isreacted with the compound of formula (XXI) as its corresponding acidadditional salt, preferably as its corresponding mono-sulfate salt.Accordingly, the acid addition salt of the compound of formula (XX)wherein X is hydrogen, a known compound or compound prepared by knownmethods is reacted with a compound of formula (XXI), a known compound orcompound prepared by known methods; wherein the compound of formula(XXI) is preferably present in an amount in the range of from about 2 toabout 4 molar equivalents, or any range therein, more preferably in anamount in the range of from about 2 to about 3 molar equivalents; inwater; to yield the corresponding compound of formula (XI).

The compound of formula (XI) may be further isolated according to knownmethods, for example by filtration, solvent evaporation, distillations,and the like; and/or optionally further purified according to knownmethods, for example by column chromatography, recrystallization, andthe like.

In an embodiment, the present invention is directed to a process for thepreparation of the compound of formula (XIa), as described in moredetail in Scheme 6, below.

Accordingly, a suitably substituted compound of formula (XX), wherein Xis hydrogen or a suitably selected nitrogen protecting group such as—C(O)—CF₃, acetyl, benzoyl, BOC, Cbz, and the like, preferably, X ishydrogen or —C(O)—CF₃; and wherein Z is selected from suitable leavinggroups such as —OMs, —O—SO₂—OH, —OTf, —OTs, and the like, and whereinboth Z substituents are the same, preferably each Z is —OMs, a knowncompound or compound prepared according to known methods;

is reacted with a compound of formula (XXIa), also known ascyclopropylamine, a known compound; wherein the compound of formula(XXIa) is preferably present in an amount in the range of from about 1to about 2 molar equivalents; in an organic solvent such as THF,toluene, DMF, 2-methyl-THF, acetonitrile, and the like, preferably THF;to yield the corresponding compound of formula (XIa).

Alternatively, when X is hydrogen, the compound of formula (XX) isreacted with the compound of formula (XXIa) as its corresponding acidadditional salt, preferably as its corresponding mono-sulfate salt.Accordingly, the acid addition salt of the compound of formula (XX)wherein X is hydrogen, a known compound or compound prepared by knownmethods is reacted with a compound of formula (XXIa), also known ascyclopropylamine, a known compound, wherein the compound of formula(XXIa) is preferably present in an amount in the range of from about 2to about 4 molar equivalents, more preferably in an amount in the rangeof from about 2 to about 3 molar equivalents; in water; to yield thecorresponding compound of formula (XIa).

The compound of formula (XIa) may be further isolated according to knownmethods, for example by filtration, solvent evaporation, distillations,and the like; and/or optionally further purified according to knownmethods, for example by column chromatography, recrystallization, andthe like. Preferably, the compound of formula (XIa) is isolated bydistillation.

In an embodiment, the present invention is directed to a process for thepreparation of the compound of formula (XIb), as described in moredetail in Scheme 7, below.

Accordingly, a suitably substituted compound of formula (XX), wherein Xis hydrogen or a suitably selected nitrogen protecting group such as—C(O)—CF₃, acetyl, benzoyl, BOC, Cbz, and the like, preferably, X ishydrogen or —C(O)—CF₃; and wherein Z is selected from suitable leavinggroups such as —OMs, —O—SO₂—OH, —OTf, —OTs, and the like, and whereinboth Z substituents are the same, preferably each Z is —OMs, a knowncompound or compound prepared according to known methods;

is reacted with a compound of formula (XXIb), also known asisopropylamine, a known compound; wherein the compound of formula (XXIb)is preferably present in an amount in the range of from about 1 to about2 molar equivalents; in an organic solvent such as THF, toluene, DMF,2-methyl-THF, acetonitrile, and the like, preferably THF; to yield thecorresponding compound of formula (XIb).

Alternatively, when X is hydrogen, the compound of formula (XX) isreacted with the compound of formula (XXIb) as its corresponding acidadditional salt, preferably as its corresponding mono-sulfate salt.Accordingly, the acid addition salt of the compound of formula (XX)wherein X is hydrogen, a known compound or compound prepared by knownmethods is reacted with a compound of formula (XXbI), also known asisopropylamine, a known compound; wherein the compound of formula (XXI)is preferably present in an amount in the range of from about 2 to about4 molar equivalents, more preferably in an amount in the range of fromabout 2 to about 3 molar equivalents; in water; to yield thecorresponding compound of formula (XI).

The compound of formula (XIb) may be further isolated according to knownmethods, for example by filtration, solvent evaporation, distillations,and the like; and/or optionally further purified according to knownmethods, for example by column chromatography, recrystallization, andthe like.

One skilled in the art will recognize that in the reactions as describedin Schemes 5, 6 and 7 above, the compounds of formula (XXI), (XXIa) or(XXIb), respectively, are acting as both a reagent and as a base. Thecompounds of formula (XXI), (XXIa) or (XXIb), respectively, and whereappropriate, may also act as a solvent.

One skilled in the art will further recognize that the reaction of thecompound of formula (XX) with the compound of formula (XXI) mayalternatively be carried out in the presence of an additional, tertiaryorganic or inorganic base such as TEA, DIPEA, pyridine, potassiumcarbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide,potassium hydroxide, and the like, and the use of said additional basepermits the use of a smaller molar amount of the compound of formula(XXI), than in the case where no additional base is added. For example,wherein 1 molar equivalent of the additional tertiary organic orinorganic base is used, then about 1 molar equivalent less of thecompound of formula (XXI) is needed.

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above.

It is anticipated that the daily dose (whether administered as a singledose or as divided doses) will be in the range 0.01 to 1000 mg per day,more usually from 1 to 500 mg per day, and most usually from 10 to 200mg per day. Expressed as dosage per unit body weight, a typical dosewill be expected to be between 0.0001 mg/kg and 15 mg/kg, especiallybetween 0.01 mg/kg and 7 mg/kg, and most especially between 0.15 mg/kgand 2.5 mg/kg.

The dosages, however, may be varied depending upon the requirement ofthe patients, the severity of the condition being treated and thecompound being employed. The use of either daily administration orpost-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders and conditions mediated by a histaminereceptor described in the present invention may also be carried outusing a pharmaceutical composition comprising any of the compounds asdefined herein and a pharmaceutically acceptable carrier. Thepharmaceutical composition may contain between about 0.1 mg and 1000 mg,preferably about 50 to 100 mg, of the compound, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, acompound of formula (I) as the active ingredient is intimately admixedwith a pharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending of the form of preparation desired for administration (e.g.oral or parenteral). Suitable pharmaceutically acceptable carriers arewell known in the art. Descriptions of some of these pharmaceuticallyacceptable carriers may be found in The Handbook of PharmaceuticalExcipients, published by the American Pharmaceutical Association and thePharmaceutical Society of Great Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders or conditions mediated by a histaminereceptor is required.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1 4-Morpholin-4-ylmethyl-benzoic acid methyl ester

A 2 L, three-neck flask fitted with a mechanical stirrer, additionfunnel, and thermocouple probe was charged with 4-formyl-benzoic acidmethyl ester (50.0 g, 0.31 mol, 1.0 eq) and 1,2-dichloroethane (700 mL).The resulting mixture was cooled to 10° C. Morpholine (53 mL, 0.61 mol,2.0 eq) was then added dropwise over 10 min. After 5 min, sodiumtriacetoxyborohydride (90 g, 0.43 mol, 1.4 eq) was added in portionsover 5 min. After stirring 30 min, the reaction mixture was warmed toroom temperature. At this point, a slow and steady temperature increasewas observed, and a water bath was used to keep the temperature of thereaction mixture below 25° C. The reaction mixture was stirred for 22hrs at room temperature. Water/ice (100 mL) was added to the reactionand the reaction mixture was stirred for 15 min. NaOH solution (1.0 M inwater, 400 mL) was added in several portions, followed by the additionof water (250 mL). The resulting mixture was stirred for 45 min. Thelayers were separated, and the aqueous layer was extracted withdichloromethane (150 mL). The combined organic layer was washed withbrine (150 mL) and then dried over Na₂SO₄. The solvent was removed invacuo to yield the title compound as a pale yellow, viscous oil.

¹H-NMR (400 MHz, CDCl₃): δ 7.99 (d, 2H, J=8.3 Hz), 7.41 (d, 2H, J=8.5Hz), 3.91 (s, 3H), 3.72-3.70 (m, 4H), 3.54 (s, 2H), 2.46-2.43 (m, 4H)

¹³C-NMR (126 MHz, CDCl₃): δ 167.0, 143.4, 129.6, 129.1, 128.9, 70.0,63.0, 53.7, 52.0

MS m/z (ESI+): 236.1 (M+H⁺).

Example 2 4-(4-Carboxy-benzyl)-morpholin-4-ium chloride

A 200 mL round-bottom flask was charged with4-morpholin-4-ylmethyl-benzoic acid methyl ester (4.0 g, 0.017 mol, 1.0eq). A solution of NaOH (2.0 g, 0.051 mol, 3.0 eq) in water was addedand the reaction mixture was stirred overnight at room temperature. NaCl(5.0 g) and HCl (6.0 M in water, 17 mL, 6.0 eq) were then added. Thereaction mixture was cooled to 0° C. and then stirred for 1 hr. Thesolid was collected by filtration, washed with pentane and dried at 50°C. under vacuum to yield the title compound as a white solid.

¹H-NMR (500 MHz, d₆-DMSO): δ 13.1 (br s, 1H), 11.8 (br s, 1H), 7.99 (d,2H, J=8.1 Hz), 7.79 (d, 2H, J=8.1 Hz), 4.40 (s, 2H), 3.92-3.83 (m, 4H),3.20-3.10 (m, 4H)

¹³C-NMR (126 MHz, d₆-DMSO): δ 167.3, 134.5, 132.2, 132.1, 130.0, 63.4,58.8, 51.2

MS m/z (ESI+): 222.1 (M+H⁺).

Example 3(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone

STEP A: A 200 mL round-bottom flask fitted with a reflux condenser wascharged with 4-(4-carboxy-benzyl)-morpholin-4-ium chloride (10.0 g,0.039 mol, 1.0 eq), toluene (50 mL), DMF (0.3 mL, 0.0039 mol, 0.1 eq),and thionyl chloride (7.1 mL, 0.097 mol, 2.5 eq) under a nitrogenatmosphere. The reaction mixture was heated to 70° C. for 6 h and thencooled to 0° C. The resulting mixture was filtered and the solid washedwith pentane to yield 4-morpholin-4-ylmethyl-benzoyl chloride, which wasused in the next step without further purification.

STEP B: A 250 mL, two-neck flask fitted with an addition funnel andthermocouple probe was charged with 1-cyclopropyl-piperazinedihydrochloride (7.1 g, 0.036 mol, 1.0 eq) and toluene (70 mL) and thencooled to 0° C. Aqueous NaOH solution (1.0 M, 70 mL, 2.0 eq) was addedat such a rate that the reaction temperature did not exceed 10° C.Na₂CO₃ powder (7.5 g, 0.071 mol, 2.0 eq) was then added to the reactionmixture. The 4-morpholin-4-ylmethyl-benzoyl chloride, prepared as inStep A above (9.8 g, 0.036 mol, 1.0 eq) was added in portions over 3minutes, while the temperature of the reaction mixture was maintainedbelow 5° C. The reaction mixture was then stirred for 2 hrs. Thereaction mixture was filtered, the layers were separated, the aqueouslayer was extracted with toluene (30 mL×2), and the combined organiclayers washed with brine (30 mL) and dried over Na₂SO₄. The solvent wasremoved in vacuo to yield the title compound as a as pale yellow viscousoil.

¹H-NMR (400 MHz, CDCl₃): δ 7.35 (br s, 4H), 3.73 (br s, 2H), 3.69 (t,4H, J=4.6 Hz), 3.50 (s, 2H), 3.37 (br s, 2H), 2.67 (br s, 2H), 2.53 (brs, 2H), 2.43 (t, 4H, J=4.2 Hz), 1.63 (ddd, 1H, J=10.3, 6.7, 3.7 Hz),0.49-0.43 (m, 2H), 0.42-0.39 (br s, 2H)

¹³C-NMR (101 MHz, CDCl₃): δ 170.6, 140.0, 135.1, 129.5, 127.5, 67.4,63.4, 54.0, 38.7, 6.3

MS m/z (ESI+): 330.2 (M+H⁺).

Example 4(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanonedihydrochloride salt

A 250 mL, three-neck flask fitted with a mechanical stirrer, additionfunnel, thermocouple probe, and heating mantle was charged with(4-cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone(11.0 g, 0.034 mol, 1.0 eq) and ethanol (75 mL). The resulting solutionwas heated to 60° C. Concentrated hydrochloric acid (6.1 mL, 0.074 mol,2.2 eq) was then added dropwise over 8 min. The reaction mixture wasthen heated at 60° C. for a further 10 min and then slowly cooled to 20°C. over 3 hrs. The resulting solid was collected by filtration, rinsedwith pentane, and dried at 50° C. for 3 hrs in a vacuum oven to yieldthe title compound as a white solid.

¹H-NMR (400 MHz, D₂O): δ 7.64 (pseudo d, J=8.3 Hz, 2H), 7.58 (pseudo d,J=8.3 Hz, 2H), 4.44 (br s, 2H), 4.20-3.10 (m, 16H), 2.88 (ddd, 1H,J=11.2, 6.6, 4.8 Hz), 1.03-0.98 (m, 4H)

¹³C-NMR (101 MHz, D₂O): δ 172.1, 135.3, 132.2, 130.9, 128.0, 64.0, 60.5,52.6, 52.4, 51.7, 44.8, 39.7, 39.5, 3.9

MS m/z (ESI+): 330.0 (M+H⁺).

Example 6(4-Cyclopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanonebis-hydrochloride salt

Step A: Preparation

A 100-L glass-lined reactor was charged with toluene (45.00 kg) andstirred at ˜20-25° C. To the stirring toluene was added4-(4-morpholinylmethyl)benzoic acid hydrochloride (6.50 kg, 93.5%, 24.04mol), 1-hydroxybenzotriazole monohydrate (2.32 kg, 15.13 mol),1-cyclopropylpiperazine (3.50 kg, 27.07 mol) and acetonitrile (9.00 kg).The resulting off-white slurry was stirred under N₂ at ˜20-25° C. for 40minutes. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride(3.50 kg, 27.07 mol) was added, followed by an acetonitrile (1.20 kg)rinse. After the addition, the reaction mixture was stirred at ˜20-25°C. overnight. Water (32.50 kg) and aqueous saturated sodium carbonate(19.50 L) were then added to the stirring suspension. The suspension wasstirred for an additional 30 minutes. The resulting biphasic solutionwas allowed to settle. The aqueous phase was discarded and the organicphase was washed with a 50% brine solution [water (19.50 L)/brine (19.50L)]. To the stirred organic phase was then added anhydrous sodiumsulfate (2.86 kg) and the resulting mixture was stirred at ˜20-25° C.for 1.5 hours. The solid sodium sulfate was filtered off and the filtercake was washed with acetonitrile (15.30 kg). The filtrate wastransferred to a clean 100-L glass-lined reactor and stirred at ˜20-25°C. Water (0.47 kg) and ⅚N HCl in 2-propanol were added to precipitatethe title compound as the corresponding bis-hydrochloride salt as asolid. The solid was filtered, washed with acetonitrile (10.2 kg) anddried (60 Torr, ˜40-45° C.) to a constant weight to yield the titlecompound as a white solid.

Step B: Purification

In a 50-L glass reactor, the white solid prepared as in Step A above(15.0 kg, 37.28 mol) was dissolved in 1:1 (v/v) mixture of ethanol:water(15.0 L:15.0 L) at ˜20-25° C. The resulting mixture was stirred for 45minutes and polish filtered (to remove any foreign particles) into aclean 100-L glass-lined reactor. The filtrate was transferred to a cleanreaction vessel. Upon stirring, (polish filtered) ethanol (75.0 L) wasadded and the title compound precipitated as a bis-HCLmono-hydrate salt.The resultant white slurry was stirred at ˜20-25° C. overnight. Thesolid was filtered, washed with ethanol (7.5 L) and dried at ˜20-25° C.under vacuum to yield the title compound as a monohydratebis-hydrochloride salt as a white solid.

Karl Fisher analysis showed 3.4-3.6% water present.

Chromatographic Purity (% w/w) showed 96.6%

Example 7 Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide

Methyltrifluoroacetate (25 g, 195.3 mmol) was added drop wise to an icecooled stirred solution of 2,2′-iminodiethanol (20.5 g, 195 mmol) inanhydrous THF (100 mL). The reaction mixture was allowed to warm toambient temperature naturally and stirred over night at ambienttemperature. The solvent was evaporated via rotary evaporation to yieldthe title compound as a clear oil.

¹H NMR (300 MHz, DMSO-d₆): 3.65 (t, J=5.4 Hz, 4H), 2.95 ((t, J=5.4 Hz,4H). MS (ESI⁺) m/z 202.14 (MH⁺).

Example 8 Methanesulfonic acid2-[(2-methanesulfonyloxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-ethylester

Trifluoro-N,N-bis-(2-hydroxy-ethyl)-acetamide (2.01 g, 10 mmol) of inTHF (12 mL) was cooled to ice bath temperature. Triethylamine (20.1 mol,2.3 g=1.56 mol) was added between 5-10° C. Methanesulphonyl chloride wasthen added to the reaction mixture at a temperature between 5-10° C. Thereaction mixture was stirred for 1 h at 5-10° C. and then allowed towarm to ambient temperature overnight. The resulting precipitated solidswere filtered off and the reaction flask was rinsed with THF (2×10 mLportions), then filtered. The filtrate was concentrated to yield thetitle compound as a clear thick oil.

¹H NMR (400 MHz, CDCl₃): (m, 4.67-4.38, 4H), 3.91-3.84 (m, 4H), 3.07 (s,3H), 3.05 (s, 3H).

Example 9 1-(4-Cyclopropyl-piperazin-1-yl)-2,2,2-trifluoro-ethanone

The product prepared as in Example 8 above, methanesulfonic acid2-[(2-methanesulfonyloxy-ethyl)-(2,2,2-trifluoro-acetyl)-amino]-ethylester (3.6 g) was dissolved in THF (18 mL). Cyclopropylamine (1.14 g, 20mmol) was then added neat to the reaction mixture. The reaction mixturewas then heated at 48° C. for 72 hours. The reaction mixture was thenconcentrated to a thick oil and the oil was chromatographed using 25-35%ethylacetate-hexanes mixture to yield the title compound as the lateeluting fraction and isolated as as thick brown oil.

¹H NMR (300 MHz, CDCl₃): 3.70-3.54 (2m, 4H), 2.68-2.65 (m, 4H),1.69-1.63 (m, 1H), 0.53-0.34 (2m, 4H)

Example 10 1-Cyclopropylpiperazine dihydrochloride

To 1-(4-cyclopropyl-piperazin-1-yl)-2,2,2-trifluoro-ethanone (444.4 mg,2 mmol) was added a mixture of HCl/IPA (5-6N, 2 mL). Solids wereobserved to precipitate immediately after the HCl/IPA was added. Theresulting suspension was stirred for 5 h. Heptane (2 mL) was then addedto the reaction mixture, followed by addition of IPA (2 mL). Theresulting suspension was stirred for 0.5 h at ambient temperature. Thesolids were filtered off using a medium glass sintered funnel with afilter paper on the top. The reaction flask was rinsed with IPA (3 mL)and the rinse was used to wash the solids. The solid was washed a secondtime with fresh IPA (2 mL). The solids were dried at ambient temperatureand house vacuum to yield the title compound as a white crystallinesolid.

¹H NMR (300 MHz, D₂O): 3.67-3.29 (2 m, 8H), 2.80-2.75 (m, 1H), 0.91-0.89(m, 4H).

Example 11 Sulfuric acid mono-[2-(2-sulfooxy-ethylamino)-ethyl]ester

Diethanolamine (10.84 g) was heated with concentrated H₂SO₄ (20.13 g) atabout 10-15 mm vacuum (house vacuum) and at a temperature in the rangeof about 175-180° C. for 5.5 h. The resulting solution was cooled toambient temperature and stirred over the weekend under nitrogen. Theresulting light brown solution was determined by ¹H NMR to contain thetitle compound in solution.

¹H NMR (300 MHz, DMSO-d₆): δ 4.5 (bs, 1H), 3.43, (t, J=6 Hz, 4H), 2.56(t, J=6 Hz, 4H).

Example 12 1-Cyclopropylpiperazine

A carousel tube was charged with sulfuric acidmono-[2-(2-sulfooxy-ethylamino)-ethyl]ester (1 g) and D₂O (3 mL). To theresulting stirred solution was added then added cyclopropylamin (0.7mL). The resulting mixture was observed to form a stirrable thickslurry, which was heated at 50° C. overnight. Comparison of the ¹H NMRof the title compound with the ¹H NMR of the dihydrochloride salt of thetitle compound confirmed that the title compound was prepared andpresent in the resulting solution.

MS (ESI⁺) m/z 127.2 (MH⁺), 275.1 (2 MW+Na).

Example 13(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanonesuccinate salt

Step A: Free Base Preparation

A 1 L three-necked flask equipped with an air stirrer and thermocouplewas charged with 4-(4-morpholinylmethyl)benzoic acid hydrochloride (50g, 0.194 mol), toluene (400 mL), acetonitrile (100 mL) and1-hydroxybenzotriazole monohydrate (17.8 g, 0.116 mol). After stirringthe resulting off-white slurry at about 20-25° C. for 5 minutes,1-isopropyl-piperazine (27.4 g, 0.213 mol) was added and the reactionmixture was stirred for 20 minutes. Next,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (44.6 g,0.233 mol) was added and the reaction mixture was stirred at about20-25° C. overnight. Water (250 mL) and aqueous saturated sodiumcarbonate (150 mL) were then added to the stirring suspension and mixedwell. The resulting biphasic mixture was allowed to settle. The aqueousphase was discarded and the organic phase was washed with a 50% brinesolution (water (150 mL)/brine (150 m L)). The organic phase was driedover anhydrous sodium sulfate, filtered, washed with acetonitrile andconcentrated to yield(4-isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone,as a free base, as a light yellow oil.

Step B: Preparation or Succinate Salt

The free base prepared as in Step A above (56.2 g, 0.17 mol) wasdissolved in ethanol (562 mL). The resulting mixture was heated to about60-65° C. Succinic acid was then added to the reaction mixture. Uponcooling to room temperature, a solid was observed to precipitate. Thesuspension was stirred for 30 minutes, then cooled to about 0-10° C. andstirred for an additional 30 minutes. The suspension was filtered, thesolid collected and dried, to yield the title compound.

The presence of the title compound was confirmed by HPLC analysis.

Example 14(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone)-bishydrochloride-monohydrate

To an 18 L reactor, equipped with an overhead stirrer, condenser withnitrogen inlet, addition funnel and a thermocouple at 20° C. was added(4-Isopropyl-piperazin-1-yl)-(4-morpholin-4-ylmethyl-phenyl)-methanone)succinate (976.4 g, 2.18 mol), 2-methyl-tetrahydrofuryl (10.8 L) and theresulting suspension was stirred. To the resulting mixture, over about10 minutes) was then added 45% aqueous KOH (597 mL, 4.80 mol) via aliquid dropping funnel and the suspension stirred to completedissolution. To the resulting mixture was added water (0.5 L) todissolve the turbid bottom layer. The phases were allowed to separateand then the bottom, aqueous layer was discarded. To the top organiclayer was added additional water (3.8 L) and the resulting mixturestirred for 0.5 h. The layers were allowed to separate and the bottomaqueous layer was discarded. The organic layer was dried with anhydrousNa₂SO₄ (500 g), stirring for 15 minutes. The organic layer was filteredto remove the solid.

To the filtered organic layer, over about 15 minutes, while maintainingthe reactor at 20° C., was added a mixture of ⅚N HCl/IPA (765 mL, 3.90mol). A solid was observed to precipitate. The resulting mixture wasstirred at 20° C. for 3.5 hours. The solids were filtered via a Büchnerfunnel covered with a Dacron cloth. The reactor was rinsed with2-methyl-tetrahydrofuran (0.5 L) and the rinse used to wash the filteredsolids. The filter cake was washed with additional2-methyl-tetrahydrofuran (0.5 L). The filter cake was allowed to air dryfor 1 h, then dried at 30° C. under vacuum (28 mm/Hg) until constantweight to yield the title compound as white crystalline solid.

Analytical Analysis: C, 54.05%, H, 8.32%, N, 9.86%, Cl⁻, 16.65%;

Karl-Fischer: 4.82%

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1.-6. (canceled)
 7. A process for the preparation of a compound offormula (XI)

wherein R¹ is selected from the group consisting of C₁₋₁₀alkyl, alkenyl,C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl, (C₃₋₈cycloalkyl)C₃₋₈alkenyland (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl; comprising

reacting a compound of formula (XX), wherein X is hydrogen or a nitrogenprotecting group and wherein both Z substituents are the same and are aleaving group, with a compound of formula (XXI), in an organic solvent,to yield the corresponding compound of formula (XI).
 8. A process forthe preparation of a compound of formula (XIa)

comprising

reacting a compound of formula (XX), wherein X is hydrogen or a nitrogenprotecting group and wherein both Z substituents are the same and are aleaving group, with a compound of formula (XXIa), in an organic solvent,to yield the corresponding compound of formula (XIa).
 9. A process forthe preparation of a compound of formula (XIb)

comprising

reacting a compound of formula (XX), wherein X is hydrogen or a nitrogenprotecting group and wherein both Z substituents are the same and are aleaving group, with a compound of formula (XXIb), in an organic solvent,to yield the corresponding compound of formula (XIb).
 10. A process forthe preparation of a compound of formula (XI)

wherein R¹ is selected from the group consisting of C₁₋₁₀alkyl, C₃₋₈alkenyl, C₃₋₈cycloalkyl, (C₃₋₈ cycloalkyl)C₁₋₆ alkyl,(C₃₋₈cycloalkyl)C₃₋₈alkenyl and (C₁₋₈ alkylcarbonyl)C₁₋₈alkyl;comprising

reacting a compound of formula (XX), wherein X is hydrogen, wherein bothZ substituents are the same and are a leaving group, and wherein thecompound of formula (XX) is present as its corresponding acid additionsalt, with a compound of formula (XXI), in water, to yield thecorresponding compound of formula (XI).
 11. A process for thepreparation of a compound of formula (XIa)

comprising

reacting a compound of formula (XX), wherein X is hydrogen, wherein bothZ substituents are the same and are a leaving group, and wherein thecompound of formula (XX) is present as its corresponding acid additionsalt, with a compound of formula (XXIa), in water, to yield thecorresponding compound of formula (XIa).
 12. A process for thepreparation of a compound of formula (XIb).

comprising

reacting a compound of formula (XX), wherein X is hydrogen, wherein bothZ substituents are the same and are a leaving group, and wherein thecompound of formula (XX) is present as its corresponding acid additionsalt, with a compound of formula (XXIa), in water, to yield thecorresponding compound of formula (XI)